US2023151034A1PendingUtilityA1
Peptidomimetic n5-methyl-n2-(nonanoyl-l-leucyl)-l-glutaminate derivatives, triazaspiro[4.14]nonadecane derivatives and similar compounds as inhibitors of norovirus and coronavirus replication
Est. expiryMar 17, 2040(~13.7 yrs left)· nominal 20-yr term from priority
C07D 273/00C07C 271/20C07D 263/10C07D 243/10A61K 31/395A61K 31/553A61K 31/222C07F 9/4018A61P 31/16C07D 211/76A61K 31/662A61P 31/00C07D 471/06C07D 267/14A61P 31/14A61P 31/12C07D 213/40C07F 9/6561C07D 487/10C07D 413/12C07D 223/16A61K 31/675
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Claims
Abstract
Peptidomimetic N5-methyl-N2-(nonanoyl-L-leucyl)-L-glutaminate derivatives, triazaspiro[4.14]nonadecane derivatives and similar compounds for use in methods of inhibiting the replication of noroviruses and coronaviruses in a biological sample or patient, for use in reducing the amount of noroviruses or coronaviruses in a biological sample or patient, and for use in treating norovirus and coronavirus in a patient, comprising administering to said biological sample or patient a safe and effective amount of a compound represented by formulae I or II, or a pharmaceutically acceptable salt thereof. The present description discloses the synthesis and characterisation of exemplary compounds as well as pharmacological data thereof (e.g. page 99 to page 271; examples 1 to 3; compounds A1 to A104 and B1 to B66; tables A to E).
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound having a structure of Formula (I), or a pharmaceutically acceptable salt thereof:
wherein
X is NR N , O, or CR 5 R 6 ;
Q is O, NR O , or a bond;
each R N is independently H or C 1-6 alkyl;
each R O is independently H or C 1-6 alkyl;
R 1 is C 1-8 alkyl, C 1-12 alkylene-C 6-10 aryl, 5- to 12-membered heterocycle having 1 to 3 ring heteroatoms selected from N, O, and S, or C 5-8 carbocyclyl, and
the C 1-12 alkylene is optionally substituted with a C 3-5 carbocycle,
the C 6-10 aryl is optionally substituted with 1-3 halo,
the 5- to 12-membered heterocycle is optionally substituted with 1-3 substituents independently selected from COO—C 1-6 alkyl, C 1-6 alkylene-C 6-10 aryl, and SO 2 —C 1-6 alkyl, and
the C 5-8 carbocyclyl is optionally substituted with C 6-10 aryl or C 6-10 aryl substituted with 1-3 halo; or
R O and R 1 together with the nitrogen to which they are attached form a 5- to 12-membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S, and optionally substituted with 1-3 halo;
R 2 is C 1-6 alkyl or C 1-6 alkylene-C 5-8 carbocyclyl, wherein C 5-8 carbocyclyl is optionally substituted with 1-3 substituents independently selected from C 1-6 alkyl and halo;
R 3 is H or C 1-6 alkyl;
R 4 is C 1-6 alkylene-OH, C 1-6 alkylene-OH substituted with PO(OCH 2 CH 2 ) 2 or SO 3 H, CHO, C(O)-(4-8 membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S, CONR A R B , or C(O)—C(O)NR N —Y 1 —X 1 -A, wherein A is C 5-8 carbocyclyl, 4-12-membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S, C 6-10 aryl, or 5-8-membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S, and the carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-2 substituents independently selected from halo, C 1-6 alkyl, and COO—C 1-6 alkyl;
Y 1 is C 1-6 alkylene optionally substituted with 1-3 substituents independently selected from halo, OH, NR N R N , and C 1-6 alkoxy;
X 1 is null, NR N R N , C(O), SO 2 , or OC(O);
R 5 and R 6 are each independently H or C 1-6 alkyl;
R 7 is C 1-6 alkyl, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-O—C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-CONH—C 1-6 alkyl, C 0-6 alkylene-CON(CH 3 ) 2 , C 1-6 alkylene-NHCONH—C 1-6 alkyl, C 1-6 alkylene-OCONH—C 1-6 alkyl, C 1-6 alkylene-NHCOO—C 1-6 alkyl, C 1-6 alkylene-NHSO 2 —C 1-6 alkyl, C 0-6 alkylene-C 6-10 aryl and the C 0-6 alkylene is optionally substituted with C 3-5 carbocyclyl, or C 1-6 alkylene-5-8 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S, wherein C 6-10 aryl and 5-8 membered heteroaryl are optionally substituted with 1-3 substituents independently selected from C 1-6 alkoxy and halo;
R 8 is H or C 1-6 alkyl; or
R 4 and R 8 together with the atoms to which they are attached form a 5- to 8-membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S, optionally substituted with 1-3 R C ; or
R 6 and R 8 together with the atoms to which they are attached form a 5- to 8-membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S, optionally substituted with CN, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-O—C 1-6 alkylene-O—C 1-6 alkyl, C 0-6 alkylene-C 6-10 aryl, or a 6-membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S, and R 7 can be H; or
R 7 and R 8 together with the nitrogen to which they are attached form a 5-12 membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S, optionally substituted with halo, C 6-10 aryl, or COO—C 1-6 alkyl;
R A and R B are each independently H, C 1-6 alkyl, or C 1-6 alkoxy; and
each R C is independently OH or CONH(C 1-6 alkyl).
2 . The compound or salt of claim 1 , wherein X is O.
3 . The compound or salt of claim 1 , wherein X is CR 5 R 6 .
4 . The compound or salt of claim 3 , wherein X is CH 2 .
5 . The compound or salt of claim 1 , wherein X is NR N .
6 . The compound or salt of any one of claims 1 to 5 , wherein each R N is H.
7 . The compound or salt of any one of claims 1 to 6 , wherein R 1 is C 1-6 alkyl.
8 . The compound or salt of any one of claims 1 to 6 , wherein R 1 is C 1-6 alkylene-C 6-10 aryl.
9 . The compound or salt of claim 8 , wherein C 1-6 alkylene is substituted with a 3-5 membered carbocycle.
10 . The compound or salt of claim 9 wherein C 6-10 aryl of R 1 is substituted with 1-3 halo.
11 . The compound or salt of claim 10 , wherein R 1 is
12 . The compound or salt of claim 10 , wherein R 1 is
13 . The compound or salt of any of claims 1 to 12 , wherein Q is a bond.
14 . The compound or salt of any of claims 1 to 12 , wherein Q is O.
15 . The compound or salt of any of claims 1 to 12 , wherein Q is NR O .
16 . The compound or salt of claim 15 , wherein R O and R 1 together with the nitrogen to which they are attached form a 5- to 12-membered heterocycle optionally substituted with 1-3 halo.
17 . The compound or salt of claim 16 , wherein R 1 -Q- is
18 . The compound or salt of any one of claims 1 to 17 , wherein R 2 is C 1-6 alkyl.
19 . The compound or salt of claim 18 , wherein R 2 is isobutyl.
20 . The compound or salt of any one of claims 1 to 17 , wherein R 2 is C 1-6 alkylene-C 5-8 carbocyclyl.
21 . The compound or salt of claim 20 , wherein C 5-8 carbocyclyl is substituted with 1-3 substituents selected from C 1-6 alkyl and halo.
22 . The compound or salt of claim 20 , wherein R 2 is
23 . The compound or salt of any one of claims 1 to 22 , wherein R 3 is H.
24 . The compound or salt of any one of claims 1 to 23 , having a structure of Formula (IA):
wherein R D is H and R E is H or C 1-6 alkyl or R D and R E together with the carbon to which they are attached form a 3-5 membered carbocycle.
25 . The compound or salt of claim 24 , wherein R D and R E are each H.
26 . The compound or salt of claim 24 , wherein R D and R E together with the carbon to which they are attached form a 3 membered carbocycle.
27 . The compound or salt of any one of claims 1 to 26 , wherein R 4 is C 1-6 alkylene-OH substituted with PO(OCH 2 CH 2 ) 2 .
28 . The compound or salt of any one of claims 1 to 26 , wherein R 4 is CHO.
29 . The compound or salt of any one of claims 1 to 26 , wherein R 4 is C(O)-(4-8 membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S.
30 . The compound or salt of any one of claims 1 to 26 , wherein R 4 is CONR A R B .
31 . The compound or salt of any one of claims 1 to 30 , wherein R 4 is C(O)—C(O)NR N —Y 1 —X 1 -A.
32 . The compound or salt of claim 31 , wherein Y 1 is C 1-6 alkylene.
33 . The compound or salt of claim 31 or 32 , wherein X 1 is null.
34 . The compound or salt of claim 31 or 32 , wherein X 1 is NR N R N , C(O), SO 2 , or OC(O).
35 . The compound or salt of any one of claims 31 to 34 , wherein A is C 5-8 carbocyclyl or C 6-10 aryl, and optionally substituted with 1-2 substituents independently selected from halo, C 1-6 alkyl, and COO—C 1-6 alkyl.
36 . The compound or salt of any one of claims 31 to 34 , wherein A is 4-12-membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S, or 5-8-membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S, optionally substituted with 1-2 substituents independently selected from halo, C 1-6 alkyl, and COO—C 1-6 alkyl.
37 . The compound or salt of claim 36 , wherein A comprises pyridyl.
38 . The compound or salt of any one of claims 30 to 37 , wherein R A is C 1-6 alkyl.
39 . The compound or salt of claim 38 , wherein R A is methyl.
40 . The compound or salt of any one of claims 30 to 39 , wherein R B is C 1-6 alkoxy.
41 . The compound or salt of claim 40 , wherein R B is methoxy.
42 . The compound or salt of any one of claims 1 to 26 , wherein R 4 and R 8 together with the atoms to which they are attached form a 6-membered heterocycle, optionally substituted with 1-3 R C .
43 . The compound or salt of claim 42 , wherein the 6-membered heterocycle is substituted with 1 or 2 R C .
44 . The compound or salt of claim 43 or 43 , wherein the 6-membered heterocycle is substituted with OH.
45 . The compound or salt of any one of claims 1 to 23 , wherein R 6 and R 8 together with the atoms to which they are attached form a 5-membered heterocycle.
46 . The compound or salt of claim 45 , wherein the heterocycle is substituted with CN, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene-O—C 1-6 alkylene-O—C 1-6 alkyl, C 0-6 alkylene-C 6-10 aryl, or a 6-membered heterocycle.
47 . The compound of claim 45 or 46 , wherein R 7 is H.
48 . The compound or salt of any one of claims 1 to 44 , wherein R 7 is C 1-6 alkyl.
49 . The compound or salt of claim 48 , wherein R 7 is methyl.
50 . The compound or salt of claim 48 , wherein R 7 is C 5 alkyl.
51 . The compound or salt of any one of claims 1 to 44 , wherein R 7 is C 1-6 alkylene-O—C 1-6 alkyl or C 1-6 alkylene-O—C 1-6 alkylene-O—C 1-6 alkyl.
52 . The compound or salt of any one of claims 1 to 51 , wherein R 7 is C 1-6 alkylene-O—C 1-6 alkyl.
53 . The compound or salt of claim 52 , wherein R 7 is C 2 alkylene-O—C 2 alkyl.
54 . The compound or salt of any one of claims 1 to 44 , wherein R 7 is C 1-6 alkylene-CONH—C 1-6 alkyl, C 1-6 alkylene-NHCONH—C 1-6 alkyl, C 1-6 alkylene-OCONH—C 1-6 alkyl, C 1-6 alkylene-NHCOO—C 1-6 alkyl, or C 1-6 alkylene-NHSO 2 —C 1-6 alkyl.
55 . The compound or salt of any one of claims 1 to 44 , wherein R 7 is C 1-6 alkylene-CONH—C 1-6 alkyl.
56 . The compound or salt of claim 55 , wherein R 7 is C 1 alkylene-CONH—C 2 alkyl.
57 . The compound or salt of any one of claims 1 to 44 , wherein R 7 is C 0-6 alkylene-C 6-10 aryl or C 1-6 alkylene-5-8 membered heteroaryl, and the aryl or heteroaryl is optionally substituted with 1-3 substituents.
58 . The compound or salt of claim 57 , wherein R 7 is C 0-6 alkylene-C 6-10 aryl.
59 . The compound or salt of claim 58 , wherein R 7 is C 1 alkylene-C 6 aryl.
60 . The compound or salt of claim 58 , wherein R 7 is C 2 alkylene-C 6 aryl.
61 . The compound or salt of any one of claims 57 to 60 , wherein C 6-10 aryl is substituted with 1 substituent selected from C 1-6 alkoxy and halo.
62 . The compound or salt of claim 46 , wherein C 6-10 aryl is substituted with chloro.
63 . The compound or salt of claim 57 , wherein R 7 is C 2 alkylene-pyridyl, optionally substituted with 1-3 substituents.
64 . The compound or salt of any one of claims 1 to 62 , wherein R 8 is C 1-6 alkyl.
65 . The compound or salt of claim 64 , wherein R 8 is methyl.
66 . The compound or salt of any one of claims 1 to 41 , wherein R 7 and R 8 together with the nitrogen to which they are attached form a 5-12 membered heterocycle.
67 . The compound or salt of claim 66 , wherein R 7 and R 8 together with the nitrogen to which they are attached form
68 . A compound having a structure of Formula (II), or a pharmaceutically acceptable salt thereof:
wherein
Y is O or a bond;
R F is H, or
R F and R 10 together with the atoms to which they are attached form a five-membered heterocycle;
R 9 is C 1-6 alkyl, or C 1-6 alkylene-C 6-10 aryl, wherein C 6-10 aryl is optionally substituted with 1-3 substituents independently selected from C 1-3 alkoxy and halo;
R 10 is H or C 1-6 alkyl;
R 11 is C 1-6 alkylene-OH, C 1-6 alkylene-OH substituted with PO(OCH 2 CH 2 ) 2 , CHO, or (CO) 1-2 NR 13 R 14 ; or
R 10 and R 11 together with the atoms to which they are attached form a six-membered heterocycle optionally substituted with 1-3 substituents independently selected from OH and CONR 13 R 14 ;
R 12 is H, C 1-6 alkyl, or C 1-6 alkylene-C 6-10 aryl, wherein C 6-10 aryl is optionally substituted with 1-3 substituents independently selected from C 1-3 alkoxy and halo;
R 13 and R 14 are each independently H, C 1-6 alkyl, or C 1-6 alkoxy;
indicates a single or a double bond; and
n is 1-3.
69 . The compound or salt of claim 68 , wherein Y is O.
70 . The compound or salt of claim 68 , wherein Y is a bond.
71 . The compound or salt of any one of claims 68 to 70 , wherein n is 1.
72 . The compound or salt of any one of claims 68 to 70 , wherein n is 2.
73 . The compound or salt of any one of claims 68 to 70 , wherein n is 3.
74 . The compound or salt of any one of claims 68 to 73 , wherein R F is H.
75 . The compound or salt of any one of claims 68 to 73 , wherein R F and R 10 together with the atoms to which they are attached form a five-membered heterocycle.
76 . The compound or salt of any one of claims 68 to 75 , having a structure of Formula (IIA), (IIB), (IIC), or (IID):
77 . The compound or salt of any one R 9 is methyl
78 . R 10 is methyl.
79 . The compound or salt of any one of claims 68 to 74 , wherein R 10 and R 11 together with the atoms to which they are attached form a six-membered heterocycle.
80 . The compound or salt of claim 79 , wherein six-membered heterocycle is substituted with 1-3 substituents independently selected from OH and CONR 13 R 14 .
81 . The compound or salt of claim 79 , wherein six-membered heterocycle is substituted with OH.
82 . The compound or salt of any one of claims 68 to 77 , wherein R 11 is C 1-6 alkylene-OH substituted with PO(OCH 2 CH 2 ) 2 .
83 . The compound or salt of any one of claims 68 to 77 , wherein R 11 is CHO.
84 . The compound or salt of any one of claims 68 to 77 , wherein R 11 is CONR 13 R 14 .
85 . The compound or salt of claim 84 , wherein R 13 is C 1-6 alkyl.
86 . The compound or salt of claim 85 , wherein R 13 is methyl.
87 . The compound or salt of any one of claims 84 to 86 , wherein R 14 is C 1-6 alkoxy.
88 . The compound or salt of claim 87 , wherein R 14 is methoxy.
89 . The compound or salt of any one of claims 68 to 88 , wherein R 12 is C 1-6 alkyl.
90 . The compound or salt of claim 71 , wherein R 12 is C 7 alkyl.
91 . The compound or salt of any one of claims 68 to 88 , wherein R 12 is C 1-6 alkylene-C 6-10 aryl.
92 . The compound or salt of any one of claims 68 to 91 , wherein indicates a single bond.
93 . The compound or salt of any one of claims 68 to 91 , wherein indicates a double bond.
94 . The compound or salt of claim 93 , wherein the double bond is cis.
95 . The compound or salt of claim 93 , wherein the double bond is trans.
96 . A compound as recited in Table A, or a pharmaceutically acceptable salt thereof.
97 . A compound as recited in Table B, or a pharmaceutically acceptable salt thereof.
98 . A compound selected from A6, A8, A10, A15, A18, A27, A57, B22, or B37, or a pharmaceutically acceptable salt thereof.
99 . A pharmaceutical formulation comprising the compound or salt of any one of claims 1 to 98 and a pharmaceutically acceptable excipient.
100 . A method for treating or preventing a viral infection in a host, comprising administering to the host a therapeutic amount of the compound or salt of any one of claims 1 to 98 .
101 . The method of claim 100 , wherein the viral infection is coronavirus infection, calicivirus infection, or picornavirus infection.
102 . The method of claim 101 , wherein the viral infection is a calicivirus infection.
103 . The method of claim 102 , wherein the calicivirus infection is a norovirus infection.
104 . The method of claim 103 , wherein the viral infection is a coronavirus infection.
105 . The method of claim 104 , wherein the coronavirus infection is severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), or Coronavirus disease 2019 (COVID-19).
106 . The method of claim 103 , wherein the viral infection is a picornavirus infection.
107 . The method of claim 102 , wherein the picornavirus infection is rhinovirus infection.
108 . The method of claim 107 wherein the rhinovirus infection is a rhinovirus A, rhinovirus B, or rhinovirus C infection.
109 . The method of claim 101 , wherein the coronavirus is an alpha coronavirus.
110 . The method of claim 101 , wherein the coronavirus is a beta coronavirus.Join the waitlist — get patent alerts
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